The present invention relates to a method for production of a tablet readily disintegrating in the oral cavity (hereinafter, referred to as xe2x80x9cintrabuccally disintegrating tabletxe2x80x9d), and to an intrabuccally disintegrating tablet which is produced by said method.
With the increase in the population of aged people, a pharmaceutical dosage form being capable of being easily taken by persons advanced in age has been desired, but many of pharmaceutical dosage forms for oral administration are conventional forms of tablets or capsules at the present, and it is not easy for aged people to swallow these dosage forms. Besides, these conventional dosage forms are often difficult to be swallowed by children or patients having poor swallowing capability. Moreover, powders or granules have also defects, for example, they need extra attention when being unpacked, or they adhere to the oral cavity when taken, and hence, they are not satisfactory enough for aged people, children or patients having poor swallowing capability, either. In order to overcome these problems, there have been studied on some tablets being easily taken without using water and being very easy for handling.
U.S. Pat. Nos. 4,371,516 and 4,305,502 (corresponding to JP-B-62-50445) disclose a method for producing a tablet, which comprising charging a suspension of a medicament, a saccharide and a gellant into a blister package of PTP (Press Through Package), subliming the water therefrom by lyophilization, and formulating tablets in said blister package. U.S. Pat. No. 5,466,464 (corresponding to PCT publication WO 93-12769) discloses a method for producing a tablet which comprises charging a suspension of a medicament, mannitol and agar into a blister package of PTP, subliming the water therefrom by drying under reduced pressure, and formulating tablets in said blister package.
U.S. Pat. No. 5,837,285 (corresponding to Japanese Patent No. 2650493, and PCT publication WO 93-15724) discloses a rapidly soluble tablet rapidly dissolving in the oral cavity, which is produced by compressing wet granules containing mainly saccharides granulated with water, and followed by drying thereof, and U.S. Pat. No. 5,501,861 (corresponding to Japanese Patent Publication JP-A-5-271054) discloses a method for producing an intrabuccally disintegrating tablet, which comprises compression-molding a mixture containing a barely sufficient amount of water to moisten the surface of particles. These methods are generally known as xe2x80x9cwet-tabletting methodxe2x80x9d.
JP-A-8-291051 and JP-A-9-48726 disclose a method for producing an intrabuccally disintegrating tablet, which comprising compression-molding a powder containing mainly a saccharide and a water-soluble binder under a low pressure, wetting the resulting tablets by placing them under humid, and drying them (hereinafter, occasionally referred to as xe2x80x9chumidification methodxe2x80x9d).
WO 93-13758 (corresponding to Japanese Patent No. 2640570) discloses a method for producing a tablet of increased strength, which comprises the steps of compression-molding a powder containing a water-soluble meltable binder such as polyethylene glycol with a low pressure, melting said water-soluble meltable binder in the resulting tablet at a temperature higher than a melting point of said water-soluble meltable binder, followed by solidifying said water-soluble meltable binder (hereinafter, occasionally referred to as xe2x80x9cheat-melting methodxe2x80x9d).
JP-A-9-316006 discloses a rapidly dissolving and disintegrating solid preparation in the oral cavity having a fresh feeling, which is improved by containing erythritol and a small amount of a solid organic acid.
On the other hand, as specific methods, WO 95-34290 discloses a method for producing a tablet, which comprises preparing shearform matrix in sheared cotton candy amorphous, making it flowable compactible micro-particulates, followed by compacting the resultant to give tablets, and WO 95-34293 and U.S. Pat. No. 5,654,003 (corresponding to Japanese Patent Publication JP-A-8-38138) disclose tablets using the above-mentioned shearform matrix.
All of the tablets explained in the above comprises saccharides, etc. as the main excipient, and they are porous tablets being capable of rapidly disintegrating, and produced by seeking how to increase the strength of tablets maintaining a porous property thereof, but they have problems such as complicated production procedures and in terms of the cost thereof, and hence, it has been desired to develop an excellent method in total aspects for producing an intrabuccally disintegrating tablet.
For example, the tablets obtained by a method disclosed in the above U.S. Pat. No. 4,371,516 (corresponding Japanese Patent Publication JP-B-62-50445) have weak strength, and they may have problems when pushed out from PTP. Moreover, said method has complicated production procedures, and requires additional equipment, and hence, it is not advantageous in view of the cost. On the other hand, although the tablets obtained by the method disclosed in WO 93-12769 have improved strength, said method has also complicated production procedures as the method disclosed in U.S. Pat. No. 4,371,516 (corresponding Japanese Patent Publication JP-B-62-50445) does, and hence, it is not advantageous in view of the cost.
Moreover, in the wet-tabletting methods disclosed in the above, wet powders tend to adhere to a die or a punch when tabletting, and it is also necessary to use an additional device to provide a prescribed amount of wet powders to the die, and hence, those methods are not suitable for continuous tabletting. Therefore, it becomes necessary to improve a tabletting machine per se in order to overcome these problems (see, JP-A-8-19589 and JP-A-8-19590).
Further, in the above-mentioned humidification methods, they need an additional step for humidifying tablets other than the conventional steps for producing tablets. In addition, these methods are not applicable to medicaments, which are unstable to humidity or tends to deliquesce under high humidity. Furthermore, the above-mentioned heat-melting methods also have problems such as that those methods are not applicable to medicaments being unstable to heat, or being incompatible with water-soluble meltable binders.
The present inventors have intensively studied in order to overcome the problems in the conventional methods, and have found an economically excellent method for producing an excellent intrabuccally disintegrating tablet having strength sufficient to take it out from a Press Through Pack and not to cause problems for the handling, as well as being capable of rapidly disintegrating in the oral cavity, by a conventional wet granulation using a solution prepared by dissolving a saccharide having a high solubility in water and a water-soluble binder in water.
According to the present invention, a method for producing an intrabuccally disintegrating tablet which comprises the following Steps (a), (b) and (c), wherein a medicament is mixed before granulation or tabletting:
(a) a step of dissolving at least one saccharide having a high solubility in water and at least one water-soluble binder in water alone or in water and an alcohol;
(b) a step of mixing the solution obtained in the above Step (a) with at least one excipient, granulating, drying and tabletting the mixture under a low compression pressure;
(c) a step of aging the tablets obtained in the above Step (b), and an intrabuccally disintegrating tablet produced by the above method are provided.
The terms used in the present specification are explained below.
In the present specification, the term xe2x80x9csaccharide having a high solubility in waterxe2x80x9d means a saccharide having relatively such a property among the so-called saccharides, and means ones having a solubility of about 40 g to about 250 g at about 25xc2x0 C. in 100 ml of purified water (hereinafter, occasionally simply referred to as xe2x80x9csolubilityxe2x80x9d, and the measurement of solubility is explained hereinbelow). These saccharides (hereinafter, occasionally referred to xe2x80x9cthe saccharide used in the present inventionxe2x80x9d) include, for example, a monosaccharide such as glucose, xylose [solubility: about 125 g; Merck Index, 12th ed., 10220 (1996)], a sugar alcohol such as xylitol, sorbitol, erythritol, and a disaccharide such as sucrose (white sugar), but erythritol, xylitol and sucrose are preferable. These saccharides can be used alone or in a mixture of two or more of these saccharides, and can usually be contained in an amount of about 0.1 to about 20% by weight, preferably in an amount of about 0.5 to about 10% by weight in the present tablet.
Thus, in the present specification, for example, mannitol and lactose have a low solubility as shown in Examples as disclosed below, and cannot fall in the category of the xe2x80x9csaccharide having a high solubility in waterxe2x80x9d of the present invention, and they are regarded as saccharides outside the saccharides used in the present invention.
The water-soluble binder includes ones which can be dissolved together with the saccharides used in the present invention in water alone or in water and an alcohol (cf. ethanol), and then, can exhibit a desired binding property, for example, polyvinylpyrrolidone, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, acacia, water-soluble gelatin, etc., and polyvinylpyrrolidone is preferable. These water-soluble binders can be used alone or in a mixture of two or more of these water-soluble binders, and can usually be contained in an amount of about 0.1 to about 20% by weight, preferably in an amount of about 0.5 to about 5% by weight in the present tablet.
Corn starch is usually used as a binder, but the dissolving rate thereof in water is low, and as a result, a tablet being prepared by using thereof shows the delay in disintegration, and hence, corn starch cannot be used as the above-mentioned water-soluble binder in the present invention.
The excipient may usually be saccharides other than saccharides used in the present invention, for example, mannitol, lactose, mannose, but the saccharides used in the present invention can also be used as an excipient.
The intrabuccally disintegrating tablets of the present invention can be applied to any medicaments which can be formulated by a conventional wet granulation or by a conventional fluidized bed granulation, for example, citrate or citrate dihydrate of mosapride disclosed in U.S. Pat. No. 4,870,074 (chemical name: (xc2x1)-4-amino-5-chloro-2-ethoxy-N-[[4-(p-fluorobenzyl)-2-morpholinyl]methyl]benzamide) (hereinafter, simply referred to as xe2x80x9cmosapride citratexe2x80x9d), alacepril (Merck Index 11th ed., 192), brotizolam (Merck Index, 11th ed., 1439), hydrochloride or tannate of berberine (Merck Index, 11th ed., 1169), and loperamide hydrochloride (Merck Index, 11th ed., 5450). The medicament can be mixed before either granulation or tabletting, and it is preferably mixed before granulation or tabletting in Step (b), more preferably before granulation in Step (b). The medicament may usually be contained in an amount of about 0.01 to about 20% by weight, preferably in an amount of about 0.1 to about 10% by weight in the present tablet.
The intrabuccally disintegrating tablet of the present invention may additionally contain a sweetening agent or a flavor in order to improve a feeling when taken, if necessary. Besides, the intrabuccally disintegrating tablet of the present invention may additionally contain a lubricant or a disintegrator which are usually necessary for conventional formulation procedures.
The tabletting procedure under a low compression pressure in Step (b) is usually carried out under a pressure of about 20 to about 300 kg/cm2, preferably under a pressure of about 50 to about 200 kg/cm2.
The drying procedure in Step (b) is preferably carried out until the surface of granules becomes dry. By the above drying, preferable flowing properties of granules are obtained.
The tablets obtained in the above Step (b) are subjected to aging in Step (c).
The xe2x80x9cagingxe2x80x9d means a step of making a pharmaceutical property of tablets, etc. to be stationary state, by which an intrabuccally disintegrating tablets having a desired strength can be obtained. The aging is usually carried out by allowing compositions to stand at room temperature (preferably at a temperature higher than about 15xc2x0 C.) for several hours to about several days, or as a positive aging, by warming compositions at a temperature higher than room temperature, preferably at a temperature higher than about 30xc2x0 C. for about 10 seconds to several days. The positive aging is preferably carried out by warming compositions at a temperature higher than about 40xc2x0 C. but lower than a softening point of a water-soluble binder used in the present invention, more preferably at a temperature of from about 40xc2x0 C. to about 80xc2x0 C., for about 1 minute to about 3 days, more preferably for about 1 minute to about 24 hours. In addition, any treatments for making the tablets etc. to be stationary state other than the methods disclosed herein can also be included in the aging procedure of the present invention.
The xe2x80x9csoftening pointxe2x80x9d means a temperature, at which a solid substance starts to soften, and can easily deform, for example, the softening point of polyvinylpyrrolidone is about 150xc2x0 C., and that of hydroxypropylcellulose is about 130xc2x0 C.
The weight of the tablets produced by the present invention may not be specified, but it is usually in the range of about 50 mg to about 500 mg, preferably in the range of about 100 mg to about 400 mg, more preferably in the range of about 150 mg to about 300 mg.
The following embodiments may be exemplified as a preferable method for producing the intrabuccally disintegrating tablets of the present invention.
A method for producing an intrabuccally disintegrating tablet, comprising the following Steps (axe2x80x2), (bxe2x80x2) and (cxe2x80x2), wherein a medicament is mixed before granulation or tabletting.
(axe2x80x2): a step of dissolving at least one saccharide selected from the group consisting of erythritol, xylitol, sorbitol, glucose and sucrose in an amount of about 0.5 to about 10% by weight, and at least one water-soluble binder selected from the group consisting of polyvinylpyrrolidone, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and water-soluble gelatin in an amount of about 0.5 to about 5% by weight, in water alone or in water and ethanol;
(bxe2x80x2): a step of mixing the solution obtained in the above Step (axe2x80x2) with at least one excipient, granulating, drying, and compressing the mixture under a low compression pressure of about 50 to about 200 kg/cm2;
(cxe2x80x2): a step of aging the tablets obtained in the above Step (bxe2x80x2) at a temperature lower than a softening point of the water-soluble binder used in the above (axe2x80x2) but higher than about 400 for about 1 minute to about 24 hours;
The method of the present invention will be illustrated in more detail below.
A saccharide used in the present invention and a water-soluble binder are dissolved in water alone, if necessary, or with adding thereto an alcohol, and an excipient is added to the solution obtained above, and further the mixture is dried after wet kneading granulation; or a saccharide used in the present invention and a water-soluble binder are dissolved in water alone, if necessary, or with adding thereto an alcohol, and the solution thus obtained is subjected to fluidized bed granulation by spraying the mixture onto a fluidized excipient, and then the granules thus obtained are dried, to give a co-dissolved mixture of the saccharide used in the present invention and the water-soluble binder. The co-dissolved mixture is in semi-solid state and can distribute uniformly in the granules, but the surface of granules is in dry state. A medicament may be added before either granulation or tabletting, but as mentioned above, a medicament is preferably added before granulation or tabletting in Step (b). Then, the granules containing said medicament or a mixture of a medicament and the granules are compressed under a low compression pressure of about 20 to about 300 kg/cm2 to give porous tablets. The porous tablets thus obtained are still not satisfactory because they can rapidly disintegrate in the oral cavity but the strength thereof is not sufficient enough. However, these tablets can be solidified by aging, for example, by allowing them to stand at room temperature for several hours to several days, or by warming them at a temperature higher than room temperature for a dozen seconds to several days, preferably at a temperature lower than a softening point of the water-soluble binder to be used but higher than about 40xc2x0 C. for about 1 minute to about 24 hours. The tablets solidified by allowing to stand under the conventional conditions or by a conventional positive aging as mentioned above have high strength being sufficient for the handling, as well as they can rapidly disintegrate in the oral cavity.
The tablets of the present invention, the methods for producing thereof, and the excellent properties of the present tablets are illustrated by the following Examples and Reference Examples, but the present invention should not be construed to be limited thereto. In addition, a method for measuring the solubility of saccharides used in the present invention is also explained below.